Project Abstract Completely noninvasive neuromodulation using focused ultrasound (FUS) offers the promise of precisely stimulating speci?c targets deep in the brain. FUS is already used to deliver precise ablations deep in the brain. A CT scan is currently used to calculate the phase aberration corrections. The focal spot is calibrated by imaging a 5C temperature rise. Both the CT scan and tissue heating are unacceptable in normal volunteers. Beyond that, skulls with similar CT scans vary widely in their ultrasound attenuation. It is imperative to accurately predict and measure the power at the focal spot and elsewhere, both for safety, and for the experimental reproducibility of the technique. The purpose of this work is to develop these critically needed tools based on MRI. Our group has studied all aspects of FUS in the brain. We have extensive experience in mapping the parameter space for FUS neuromodulation, in measuring the FUS beam in brain using temperature and MR acoustic radiation force imaging, and in determining the beam focusing weights for large FUS arrays for focusing FUS through the skull. Our goal is to direct this expertise into turning FUS neuromodulation into a widely available, repeatable, and accurate research tool that would be safe for normal volunteers. With these calibration and targeting tools in hand, we can answer the important question of what physical effect the ultrasound is creating that stimulates the brain. Our work in the mouse points to the cavitation index or particle displacement, while work in the retina points to radiation force. This is the central question in FUS neuromodulation. We need to know what physical effect to create in the brain to produce neuromodulation in humans. We propose to answer this question in the porcine model, which is physiologically very close to humans in terms of skull thickness. Unlike our rodent studies, where behavior was monitored by means of EMG electrodes in the forelimbs, we will employ more sensitive fMRI to measure the response in the brain, speci?cally the visual cortex, while sonicating a deep structure, speci?cally the lateral geniculate nucleus (LGN). At the end of this project, we will have developed all of the technologies required to make FUS a safe and repeatable neuroscience research tool for studying normal volunteers. We will be able to focus the FUS array based on MRI, and accurately predict ultrasound intensities and temperatures at the target and throughout the brain. We will also have a much better understanding of the biophysical basis of FUS neuromodulation, which will allow us to optimize the FUS stimulation protocol.